1. Field of Invention
This invention relates to novel 1-phenyl-7-substituted-aminohept-5-yn-2-ones optionally mono-or di-substituted at the 1-position, their pharmaceutically acceptable salts, their use in the treatment of neurogenic bladder disease and methods for their manufacture.
2. State of the Art
Neurogenic bladder disease is defined as a disorder involving loss of control of urinatior. The major symptoms can be urinary frequency, urinary retention or incontinence.
There are two types of lesions that come under the rubric of neurogenic bladder. The first, upper motoneuron lesion, leads to hypertonia and hyperreflexia of the bladder, a spastic condition, giving rise to symptoms of urinary frequency and incontinence. The second lesion, a lower motoneuron lesion, involves hypotonia and hyporeflexia of the bladder, and in more severe conditions complete distension and atonia of the bladder muscle. Thus, this is a flaccid condition. The major symptoms in this condition are urinary retention, since the voiding reflex has been lost, and incontinence, which occurs when the bladder "leaks", being full to overflowing.
The flaccid or hypotonic bladder is the easier condition to treat. The aim in treatment is to produce a contraction of the bladder, while avoiding contraction of the bladder neck or the urethra. Parasympathomimetic compounds (cholinergic agonists) are commonly employed to stimulate the excitatory muscarinic receptor on the bladder smooth muscle. The most widely used compound in this class is bethanechol, a muscarinic receptor agonist. This is given in combination with the alpha-adrenergic antagonist phenoxybenzamine to prevent sympathetic stimulation of the bladder neck muscle. Bethanechol is also sometimes given in combination with baclofen, a skeletal muscle receptor antagonist. In general, however, urologists and internists have been moving away from pharmacological treatment of the hypotonic bladder, and prefer to institute the physical maneuver of intermittent catheterization.
The majority of neurogenic bladder patients have the spastic or hypertonic condition, which is usually more difficult to treat. In this instance, the usual aim of the clinician is to attempt to convert the condition of hyperreflexia and hypertonia to hypotonia, thereby treating the primary problem of incontinence. When the condition has been converted to hypotonia it can be straightforwardly managed by intermittent catheterization. There is a significant population of patients who cannot be converted completely from the hypertonic to the hypotonic condition, and who still find that they have to urinate every hour. For these patients, longer term treatment with an anticholinergic drug (muscarinic receptor antagonist) is necessary. The current drug of choice is oxybutynin, which is considered to be better than older anticholinergic treatments such as methantheline and propantheline. Although relatively high doses of oxybutynin are in general use (5 mg q.i.d.), tachycardia is not a major side effect of this compound, unlike classical muscarinic receptor antagonists such as atropine. On the other hand, the most frequent side effect of oxybutynin treatment is dry mouth.
Recent advances in the muscarinic receptor field have suggested that oxybutynin is an antagonist with a fair degree of selectivity for the M.sub.1 -AChR type of receptor, thereby explaining both the lack of cardiac side effects (heart tissue has predominantly M.sub.2 -AChR) and the occurrence of the dry mouth side effect (salivary glands have predominantly an M.sub.1 -AChR population).
Although oxybutynin chloride is used in the treatment of neurogenic bladder disorder, it exhibits a relatively short duration of action and, as indicated above, causes dry mouth. The compounds of the present invention contain a methylene group in lieu of the non-carbonyl (i.e., esteratic) oxygen of oxybutynin chloride. These novel compounds exhibit advantages relative to oxybutynin chloride in terms of their efficacy and specificity of action against neurogenic bladder disorder. In particular, the compounds of the invention are longer acting antimuscarinic agents which have spasmolytic action.